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Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure–activity relationship modeling

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Abstract

Several Pt(IV) complexes of the general formula [Pt(L)2(L′)2(L″)2] [axial ligands L are Cl−, RCOO−, or OH−; equatorial ligands L′ are  two am(m)ine or one diamine; and equatorial ligands L″ are Cl− or glycolato] were rationally designed and synthesized in the attempt to develop a predictive quantitative structure–activity relationship (QSAR) model. Numerous theoretical molecular descriptors were used alongside physicochemical data (i.e., reduction peak potential, E p, and partition coefficient, log P o/w) to obtain a validated QSAR between in vitro cytotoxicity (half maximal inhibitory concentrations, IC50, on A2780 ovarian and HCT116 colon carcinoma cell lines) and some features of Pt(IV) complexes. In the resulting best models, a lipophilic descriptor (log P o/w or the number of secondary sp 3 carbon atoms) plus an electronic descriptor (E p, the number of oxygen atoms, or the topological polar surface area expressed as the N,O polar contribution) is necessary for modeling, supporting the general finding that the biological behavior of Pt(IV) complexes can be rationalized on the basis of their cellular uptake, the Pt(IV) → Pt(II) reduction, and the structure of the corresponding Pt(II) metabolites. Novel compounds were synthesized on the basis of their predicted cytotoxicity in the preliminary QSAR model, and were experimentally tested. A final QSAR model, based solely on theoretical molecular descriptors to ensure its general applicability, is proposed.

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References

  1. Lippert B (1999) Cisplatin—chemistry and biochemistry of a leading anticancer drug. Wiley, Weinheim

    Book  Google Scholar 

  2. Kaufmann GB, Molayem E (1990) Platinum Met Rev 34:215–221

    Google Scholar 

  3. Rosenberg B, VanCamp L, Krigas T (1965) Nature 205:698–699

    Article  CAS  PubMed  Google Scholar 

  4. Hall MD, Dolman RD, Hambley TW (2004) Metal complexes in tumor diagnosis and as anticancer agents. In: Sigel A, Sigel H (eds) Metal ions in biological systems, vol 42. Dekker, New York, pp 298–322

  5. Christian MC, Spriggs D, Tutsc KD, O’Rourke T, VonHoff DD, Jacob JL, Reed E (1991) In: Howell SB (ed) Platinum and other metal coordination compounds in cancer chemotherapy. Plenum Press, New York, pp 453–459

  6. Bramwell VHC, Crowther D, O’Malley S, Swindell R, Johnson R, Cooper EH, Thatcher N, Howell A (1985) Cancer Treat Rep 69:409–416

    CAS  PubMed  Google Scholar 

  7. Pawinski A, Crowther D, Keizer HJ, Voute PA, Somers R, van Glabbeke M, Lentz MA, van Oosterom AT (1999) Eur J Cancer 35:163–164

    Article  CAS  PubMed  Google Scholar 

  8. Pasetto LM, D’Andrea MR, Brandes AA, Rossi E, Monfardini S (2006) Crit Rev Oncol Hematol 60:59–75

    Article  PubMed  Google Scholar 

  9. Kozubík A, Vaculová A, Souček K, Vondráček J, Turánek J, Hofmanová J (2008) Met Based Drugs 417897. doi:10.1155/2008/417897

  10. Hall MD, Alderden RA, Zhang M, Beale PJ, Cai Z, Lai B, Stamp APJ, Hambley TW (2006) J Struct Biol 155:38–44

    Article  CAS  PubMed  Google Scholar 

  11. Hall MD, Mellor HR, Callaghan R, Hambley TW (2007) J Med Chem 50:3403–3411

    Article  CAS  PubMed  Google Scholar 

  12. Montaña AM, Batalla C (2009) Curr Med Chem 16:2235–2260

    Article  PubMed  Google Scholar 

  13. Choi S, Filotto C, Bisanzo M, Delaney S, Lagasee D, Whitworth JL, Jusko A, Li CR, Wood NA, Willingham J, Schwenker A, Spaulding K (1998) Inorg Chem 37:2500–2504

    Article  CAS  Google Scholar 

  14. Hambley TW, Battle AR, Deacon GB, Lawrenz ET, Fallon GD, Gatehouse BM, Webster LK, Rainone S (1999) J Inorg Biochem 77:3–12

    Article  CAS  PubMed  Google Scholar 

  15. Battle AR, Deacon GB, Dolman RC, Hambley TW (2002) Aust J Chem 55:699–704

    Article  CAS  Google Scholar 

  16. Talman EG, Kidani Y, Mohrmann L, Reedijk J (1998) Inorg Chim Acta 283:251–255

    Article  CAS  Google Scholar 

  17. Gibson D (2009) Dalton Trans 10681–10689

  18. Fojo T, Farrell N, Ortuzar W, Tanimura H, Weinstein J, Myers TG (2005) Crit Rev Oncol Hematol 53:25–34

    Article  PubMed  Google Scholar 

  19. Hall MD, Amjadi S, Zhang M, Beale PJ, Hambley TW (2004) J Inorg Biochem 98:1614–1624

    Article  CAS  PubMed  Google Scholar 

  20. Heudi O, Mercier-Jobard S, Cailleux A, Allain P (1999) Biopharm Drug Dispos 20:107–116

    Article  CAS  PubMed  Google Scholar 

  21. Dhara SC (1970) Indian J Chem 8:193–194

    Google Scholar 

  22. Giandomenico CM, Abrams MJ, Murrer BA, Vollano JF, Rheinheimer MI, Wyer SB, Bossard GE, Higgins JD III (1995) Inorg Chem 34:1015–1021

    Article  CAS  PubMed  Google Scholar 

  23. Totani T, Aono K, Komura M (1985) Glycolic acid platinum complexes. US Patent 4,560,781, 24 Dec 1985

  24. Peloso A (1983) J Chem Soc Dalton Trans 1285–1289

  25. Barnes KR, Kutikov A, Lippard SJ (2004) Chem Biol 11:557–564

    Article  CAS  PubMed  Google Scholar 

  26. Shamsuddin S, Santillan CC, Stark JL, Whitmire KH, Siddik ZH, Khokhar AR (1998) J Inorg Biochem 71:29–35

    Article  CAS  PubMed  Google Scholar 

  27. Alley MC, Scudiero DA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Cancer Res 48:589–601

    CAS  PubMed  Google Scholar 

  28. Hypercube (2000) HYPERCHEM 7.03 for Windows. Hypercube, Gainesville

  29. Todeschini R, Ballabio D, Consonni V, Mauri A, Pavan M (2008) DRAGON software for the calculation of molecular descriptors, version 5.5 for Windows. Talete, Milan. http://www.talete.mi.it/

  30. Todeschini R, Consonni V, Mauri A, Pavan M (2003) In: Leardi, R (ed) Nature-inspired methods in chemometrics: genetic algorithms and artificial neural networks. Elsevier, Amsterdam, pp 141–167

  31. Todeschini R, Ballabio D, Consonni V, Mauri A, Pavan M (2008) MOBY DIGS-models by descriptors in genetic selection, version 1.0 beta for Windows. Talete, Milan. http://www.talete.mi.it/

  32. Lindgren F, Hansen B, Karcher W, Sjöström M, Eriksson L (1996) J Chemom 10:521–532

    Article  CAS  Google Scholar 

  33. Gramatica P (2007) QSAR Comb Sci 26:694–701

    Article  CAS  Google Scholar 

  34. Consonni V, Ballabio D, Todeschini R (2009) J Chem Inf Model 49:1669–1678

    Article  CAS  PubMed  Google Scholar 

  35. Atkinson AC (1985) Plots, transformations and regression. Clarendon Press, Oxford

    Google Scholar 

  36. Reisner E, Arion VB, Keppler BK, Pombeiro AJL (2008) Inorg Chim Acta 361:1569–1583

    Article  CAS  Google Scholar 

  37. Lambert WJ (1993) J Chromatogr A 656:469–484

    Article  CAS  Google Scholar 

  38. Braumann T (1986) J Chromatogr 373:191–225

    Article  CAS  PubMed  Google Scholar 

  39. Platts JA, Oldfield SP, Reif MM, Palmucci A, Gabano E, Osella D (2006) J Inorg Biochem 100:1199–1207

    Article  CAS  PubMed  Google Scholar 

  40. Ali Khan SR, Huang S, Shamsuddin S, Inutsuka S, Whitmire KH, Siddik ZH, Khokhar AR (2000) Bioorg Med Chem 8:515–521

    Article  CAS  PubMed  Google Scholar 

  41. Kelland LR, Murrer BA, Abel G, Giandomenico CM, Mistry P, Harrap KR (1992) Cancer Res 52:822–828

    CAS  PubMed  Google Scholar 

  42. Nasal A, Siluk D, Kaliszan R (2003) Curr Med Chem 10:381–426

    CAS  PubMed  Google Scholar 

  43. Hawkins DM (2004) J Chem Inf Comput Sci 44:1–12

    CAS  PubMed  Google Scholar 

  44. Platts JA, Hibbs DE, Hambley TW, Hall MD (2001) J Med Chem 44:472–474

    Article  CAS  PubMed  Google Scholar 

  45. Caron G, Ermondi G, Gariboldi MB, Monti E, Gabano E, Ravera M, Osella D (2009) ChemMedChem 4:1677–1685

    Article  CAS  PubMed  Google Scholar 

  46. Tropsha A, Gramatica P, Gombar VK (2003) QSAR Comb Sci 22:69–77

    Article  CAS  Google Scholar 

  47. Nemirovski A, Vinograd I, Takrouri K, Mijovilovich A, Rompel A, Gibson D (2010) Chem Commun 46:1842–1844

    Article  CAS  Google Scholar 

  48. Bryce NS, Zhang JZ, Whan RM, Yamamoto N, Hambley TW (2009) Chem Commun 2673–2675

  49. Mellor HR, Snelling S, Hall MD, Modok S, Jaffar M, Hambley TW, Callaghan R (2005) Biochem Pharmacol 70:1137–1146

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Financial support for this work was from the Regione Piemonte (CIPE 2006 project-code A 370 and Ricerca Sanitaria Finalizzata 2009) and the ATF Association (Alessandria, Italy). The research was carried out within the framework of the European Cooperation COST D39 (Metallo-Drug Design and Action) and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici (CIRCMSB, Bari, Italy).

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Authors and Affiliations

  1. QSAR Research Unit in Environmental Chemistry and Ecotoxicology, Department of Structural and Functional Biology, Università dell’Insubria, Via Dunant 3, 21100, Varese, Italy

    Paola Gramatica, Ester Papa & Mara Luini

  2. Section of Pharmacology, Department of Structural and Functional Biology, Università dell’Insubria, Via A. da Giussano 10, 21052, Busto Arsizio (VA), Italy

    Elena Monti & Marzia B. Gariboldi

  3. Department of Environmental and Life Sciences, Università del Piemonte Orientale “A. Avogadro”, Viale Michel 11, 15121, Alessandria, Italy

    Mauro Ravera, Elisabetta Gabano, Luca Gaviglio & Domenico Osella

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  1. Paola Gramatica
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  2. Ester Papa
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  3. Mara Luini
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  4. Elena Monti
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  5. Marzia B. Gariboldi
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  7. Elisabetta Gabano
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  9. Domenico Osella
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Correspondence to Domenico Osella.

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Gramatica, P., Papa, E., Luini, M. et al. Antiproliferative Pt(IV) complexes: synthesis, biological activity, and quantitative structure–activity relationship modeling. J Biol Inorg Chem 15, 1157–1169 (2010). https://doi.org/10.1007/s00775-010-0676-4

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  • DOI: https://doi.org/10.1007/s00775-010-0676-4

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